Relapsing fever is a spirochetal infection caused by Borrelia species, transmitted by soft ticks (tick-borne relapsing fever, TBRF — B. hermsii, B. turicatae), hard ticks (hard-tick relapsing fever — B. miyamotoi), or body lice (louse-borne relapsing fever, LBRF — B. recurrentis). The hallmark is recurrent episodes of high fever separated by afebrile intervals, with thrombocytopenia as the most suggestive laboratory finding. [1-2] Case fatality rates range from 4–10% and the Jarisch-Herxheimer reaction (JHR) is a critical treatment-related complication. [1][3]
1. History
- Fever pattern: Abrupt onset of high fever lasting 3–6 days, followed by crisis (drenching sweats, defervescence), then afebrile interval of ~7 days before relapse; typically 3–5 relapses if untreated [3]
- Incubation: ~7 days for TBRF; 2–18 days for LBRF [4-5]
- Exposure history: Sleeping in rustic cabins, lean-tos, or caves in western US states (TBRF); rodent cohabitation; travel to endemic areas (Horn of Africa for LBRF); refugee camp exposure; caving in Texas [4]
- Tick bite recall: Often absent — Ornithodoros soft ticks feed briefly at night and bites are painless [4]
- Associated symptoms: Headache, myalgias, arthralgias, chills/rigors, nausea/vomiting, dizziness [2]
- Important negatives: Absence of erythema migrans (distinguishes from Lyme), no eschar
2. Alarm Features
- Neurologic involvement (5–10% of TBRF): meningoencephalitis, cranial neuritis, facial palsy, altered mental status [2-3]
- ARDS — rare but life-threatening complication [2]
- Severe thrombocytopenia with life-threatening bleeding (epistaxis, GI hemorrhage) [6]
- Myocarditis and acute pulmonary edema (especially LBRF) [5]
- Hyperpyrexia, shock, hepatic failure [5]
- Pregnancy: spontaneous abortion, transplacental transmission, neonatal death [1-2]
- Jarisch-Herxheimer reaction post-treatment: rigors, fever spike, tachycardia, hypotension — occurs in ~19% of TBRF and ~56% of LBRF cases [1][7]
3. Medications
First-line treatment: [3-4]
- Doxycycline 100 mg PO BID × 5–10 days (adults, uncomplicated TBRF)
- Tetracycline 500 mg PO QID × 10 days (alternative)
- Erythromycin 500 mg PO QID × 10 days (tetracycline-allergic or pediatric patients)
- Pediatric: Erythromycin 12.5 mg/kg QID × 10 days [4]
Neurologic involvement or pregnancy: Parenteral ceftriaxone 2 g IV daily × 10–14 days [2][4]
LBRF: Single-dose tetracycline or penicillin may suffice, though tetracycline has lower relapse rates but higher JHR risk [7]
Cautions
- Penicillin G associated with increased relapse rates in TBRF [3]
- Amoxicillin — B. miyamotoi demonstrates in vitro resistance; avoid as monotherapy for hard-tick relapsing fever [8]
- All patients must be observed for 4 hours after first antibiotic dose for JHR [2]
- JHR management is supportive (IV fluids, vasopressors if needed); anti-TNF-α Fab has shown efficacy in LBRF but is not widely available; meptazinol may diminish JHR severity [9-10]
4. Diet
- No specific dietary triggers or restrictions
- Hydration is critical during febrile episodes given high insensible losses from rigors and drenching sweats
- Maintain adequate oral intake; IV fluids if unable to tolerate PO or hemodynamically unstable
5. Review of Systems
- Neurologic: Headache, neck stiffness, facial droop, vision changes, confusion, seizures
- Musculoskeletal: Myalgias, arthralgias
- GI: Nausea, vomiting, abdominal pain, diarrhea, anorexia
- Respiratory: Dyspnea, cough (consider ARDS)
- Hematologic: Epistaxis, easy bruising, petechiae (thrombocytopenia)
- Dermatologic: Petechial, macular, or papular rash (4–50% of cases, typically as primary fever wanes) [3]
- Ophthalmologic: Iritis, uveitis (ocular manifestations of borreliosis) [2]
6. Collateral History and Family History
- Travel companions: Others with similar symptoms (cluster outbreaks in cabins, refugee camps, prisons) [4][6]
- Occupational/recreational exposure: Outdoor workers, spelunkers, hikers in western US
- Living conditions: Overcrowding, poor hygiene (LBRF); rodent-infested dwellings (TBRF)
- Immigration/refugee status: Recent arrival from Horn of Africa raises suspicion for LBRF [5]
- No significant hereditary predisposition; family history is relevant only for shared exposures
7. Risk Factors
- TBRF: Sleeping in rodent-infested rustic cabins in western US (AZ, CA, CO, ID, MT, NV, NM, OR, TX, UT, WA, WY); caving in Texas [4]
- LBRF: Overcrowding, poor hygiene, homelessness, refugee camps, prisons in endemic areas (Ethiopia, East Africa) [5-6]
- Hard-tick RF (B. miyamotoi): Ixodes tick exposure in northeastern/upper midwestern US; immunocompromised patients at risk for severe disease [2]
- Seasonality: Summer and autumn predominance [11]
- Pregnancy: Higher risk of severe complications and perinatal mortality [1][5]
- Extremes of age: Infants and elderly at highest mortality risk [3]
8. Differential Diagnosis
- Malaria — most critical to exclude in travelers with relapsing fevers; thick/thin smear
- Leptospirosis — conjunctival suffusion, renal failure, jaundice; water exposure history [5]
- Human granulocytic anaplasmosis — especially mimics B. miyamotoi infection; leukopenia, thrombocytopenia, elevated transaminases [12]
- Ehrlichiosis — similar tick-borne febrile illness with cytopenias [13]
- Rocky Mountain spotted fever — rash pattern (wrists/ankles → trunk), petechiae [4]
- Babesiosis — hemolytic anemia, ring forms on smear; coinfection possible [13]
- Lyme disease — erythema migrans distinguishes; serologic cross-reactivity exists [2][12]
- Brucellosis — undulant fever, night sweats, travel to endemic areas
- Typhoid fever — stepwise fever, travel history, rose spots
- Endocarditis — relapsing fevers, new murmur, embolic phenomena
9. Past Medical History
- Immunocompromised states: HIV, transplant, chemotherapy — increased risk of severe B. miyamotoi disease (meningoencephalitis) [2]
- Asplenia: Increased susceptibility to spirochetal and tick-borne infections
- Prior episodes: Relapses are characteristic; prior relapsing fever does not confer lasting immunity due to antigenic variation [5]
- Pregnancy status: Must be assessed — alters treatment (ceftriaxone preferred) and carries high perinatal risk [2]
10. Physical Exam
- Vital signs: High fever (often >39°C), tachycardia; hypotension during crisis phase or JHR
- General: Acutely ill, diaphoretic, rigors
- HEENT: Epistaxis (common in LBRF — 83% in one series); conjunctival injection; iritis [6]
- Skin: Petechial, macular, or papular rash (4–50%); jaundice (especially LBRF) [3][5]
- Abdomen: Hepatosplenomegaly; splenic tenderness (beware ruptured spleen) [5]
- Neurologic: Cranial nerve palsies (especially CN VII), meningismus, altered sensorium [2-3]
- Cardiopulmonary: Signs of myocarditis, pulmonary edema, or ARDS in severe cases [5]
11. Lab Studies
- CBC: Thrombocytopenia (most suggestive lab finding — 61% in one LBRF series); leukocytosis with left shift or leukopenia; anemia [1][6]
- Peripheral blood smear (Wright or Giemsa stain): Spirochetes visible during febrile episodes — sensitivity ~70% during fever; enhanced by acridine orange staining or dark-field microscopy [3]
- CRP/ESR: Elevated [11]
- LFTs: Elevated transaminases, elevated bilirubin [4]
- Coagulation: Prolonged PT/PTT [4]
- BMP: Assess renal function, electrolytes
- Blood cultures: Borrelia can be cultured in special media (BSK-H) but not rapid or widely available [3]
- PCR (NAAT): More sensitive than microscopy; can detect and differentiate RF Borrelia species; should be performed early, ideally before treatment [2][14]
- Serology (IFA, EIA): Available but not standardized; cross-reacts with B. burgdorferi (Lyme); most useful with paired acute/convalescent samples [2-3]
12. Imaging
- Chest X-ray: If respiratory symptoms present — evaluate for ARDS, pulmonary edema [2][5]
- CT head: If neurologic symptoms — evaluate for meningoencephalitis, cerebral hemorrhage
- Abdominal ultrasound: If abdominal pain or concern for hepatosplenomegaly/splenic rupture
- Echocardiography: If signs of myocarditis or heart failure
- Routine imaging is not necessary in uncomplicated cases
13. Special Tests
- Peripheral blood smear during febrile episode — the diagnostic gold standard in most clinical settings [1][12]
- PCR/NAAT: Semimultiplex real-time PCR can simultaneously detect and classify RF borreliae into soft-tick, hard-tick, and louse-borne groups [14]
- Dark-field microscopy or phase-contrast microscopy of wet-mount preparations — enhances sensitivity [3]
- Acridine orange staining of fixed smears — increases spirochete detection [3]
- Lumbar puncture: If meningoencephalitis suspected — CSF pleocytosis, elevated protein; spirochetes may be visualized or detected by PCR
14. ECG
- Obtain ECG if myocarditis suspected (chest pain, dyspnea, new heart failure)
- Possible findings: Sinus tachycardia, ST-T wave changes, conduction abnormalities
- Monitor during JHR — tachycardia and hypotension are hallmarks [3]
- QTc prolongation may occur with severe electrolyte derangements from dehydration
15. Assessment
Relapsing fever is a spirochetal infection characterized by recurrent febrile episodes due to antigenic variation of borrelial outer-membrane lipoproteins. [5] Severity generally decreases with each relapse if untreated. [3] Key clinical pearls:
- Typical presentation: Abrupt high fever + headache + myalgias + thrombocytopenia in a patient with relevant exposure history
- Atypical presentations: B. miyamotoi may present as nonspecific acute febrile illness without classic relapses (relapsing fever in only 10–40% of cases) [2]
- Complications: Neurologic (5–10%), hemorrhagic (severe thrombocytopenia), ARDS, hepatic failure, myocarditis, JHR [1-3]
- Case fatality: TBRF ~6.5%, LBRF 4–10% (historically up to 40% untreated in epidemics) [1][5]
16. Treatment Plan
Initial stabilization
- IV access, fluid resuscitation if hemodynamically unstable
- Antipyretics for symptomatic relief
Antibiotic therapy: [2-4]
- Uncomplicated TBRF (adults): Doxycycline 100 mg PO BID × 5–10 days
- Uncomplicated TBRF (children): Erythromycin 12.5 mg/kg QID × 10 days
- Neurologic involvement or pregnancy: Ceftriaxone 2 g IV daily × 10–14 days
- LBRF: Single-dose tetracycline 500 mg or procaine penicillin may suffice
JHR prophylaxis/management: [2-3][9]
- Observe all patients for 4 hours after first antibiotic dose
- Supportive care: IV fluids, vasopressors for refractory hypotension
- Anti-TNF-α Fab reduced JHR incidence from 90% to 50% in one RCT of LBRF (not widely available) [9]
- Corticosteroids have not been shown to prevent JHR [10]
LBRF-specific: Delousing of patient and contacts; pediculicide treatment; clothing sterilization [5]
17. Disposition
Admit if
- Hemodynamic instability, severe sepsis
- Neurologic involvement (meningoencephalitis, cranial neuropathy)
- Severe thrombocytopenia with active bleeding
- Pregnancy (high-risk for complications; requires IV therapy and monitoring)
- Inability to tolerate oral medications
- Need for JHR monitoring in high-risk patients (LBRF, first treatment dose)
- ARDS, myocarditis, hepatic failure
Observation
Discharge if
- Clinically stable after observation period
- Tolerating oral antibiotics
- Reliable follow-up arranged
- No alarm features
Consult infectious disease for: neurologic involvement, pregnancy, diagnostic uncertainty, severe or complicated cases
18. Follow Up / Return Precautions
- Follow-up: Within 48–72 hours of discharge to reassess clinical response; repeat CBC to monitor platelet recovery
- Expected course: Fever typically resolves within 24–48 hours of antibiotic initiation; severity decreases with each relapse [3]
- Return immediately for:
- Recurrence of high fever after completing antibiotics (treatment failure/relapse)
- New neurologic symptoms (headache with neck stiffness, facial droop, confusion, vision changes)
- Bleeding (epistaxis, blood in stool, easy bruising)
- Shortness of breath, chest pain
- Signs of JHR if recently started antibiotics (rigors, feeling faint, rapid heartbeat)
- Patient counseling: Explain the relapsing nature of the disease; emphasize completing full antibiotic course; advise on tick/louse prevention measures for future exposures
- Public health: TBRF is reportable in many US states; LBRF outbreaks require public health notification for delousing and contact management [5-6]
References
1. Tick Borne Relapsing Fever - A Systematic Review and Analysis of the Literature. — Jakab Á, Kahlig P, Kuenzli E, Neumayr A. PLoS Neglected Tropical Diseases. 2022.
2. Tickborne Diseases of the United States: A Reference Manual for Healthcare Providers Sixth Edition. — Nancy Shadick MD MPH, Nancy Maher MPH, Dennis Hoak MD United States Centers for Disease Control and Prevention (2022). 2022.
3. Tick-Borne Diseases in the United States. — Spach DH, Liles WC, Campbell GL, et al. The New England Journal of Medicine. 1993.
4. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Management of Tick-Borne Illness in the United States. — Ho BM, Davis HE, Forrester JD, et al. Wilderness & Environmental Medicine. 2021.
5. Louse-Borne Relapsing Fever (Borrelia Recurrentis Infection). — Warrell DA. Epidemiology and Infection. 2019.
6. Epistaxis and Thrombocytopenia as Major Presentations of Louse Borne Relapsing Fever: Hospital-Based Study. — Abera EG, Tukeni KN, Didu GH, et al. PloS One. 2022.
7. Comparison of Antibiotic Regimens for Treating Louse-Borne Relapsing Fever: A Meta-Analysis. — Guerrier G, Doherty T. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2011.
8. Susceptibility of the Relapsing-Fever Spirochete Borrelia Miyamotoi to Antimicrobial Agents. — Koetsveld J, Draga ROP, Wagemakers A, et al. Antimicrobial Agents and Chemotherapy. 2017.
9. Prevention of Jarisch–Herxheimer Reactions by Treatment with Antibodies against Tumor Necrosis Factor α. — Fekade D, Knox K, Hussein K, et al. The New England Journal of Medicine. 1996.
10. Meptazinol Diminishes the Jarisch-Herxheimer Reaction of Relapsing Fever. — Teklu B, Habte-Michael A, Warrell DA, White NJ, Wright DJ. Lancet. 1983.
11. Epidemiology of Tick-Borne Relapsing Fever in Endemic Area, Spain. — Domínguez MC, Vergara S, Gómez MC, Roldán ME. Emerging Infectious Diseases. 2020.
12. Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2024 Update by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). — Miller JM, Binnicker MJ, Campbell S, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2024.
13. Fever of Unknown Origin. — Haidar G, Singh N. The New England Journal of Medicine. 2022.
14. Simultaneous Detection and Differentiation of Clinically Relevant Relapsing Fever With Semimultiplex Real-Time PCR. — Dietrich EA, Replogle AJ, Sheldon SW, Petersen JM. Journal of Clinical Microbiology. 2021.